Effects of Low-Dose Prednisolone on Hepatic and Peripheral Insulin Sensitivity, Insulin Secretion, and Abdominal Adiposity in Patients With Inflammatory Rheumatologic Disease

Abstract

OBJECTIVEThe metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations.RESEARCH DESIGN AND METHODSSubjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography.RESULTSPrednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different.CONCLUSIONSLow-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…However, in contrast to the above-mentioned inhibitory effects observed in both acute and long-term GC incubation, chronic in vivo administration of these steroids leads to up-regulation of b-cell function as a result of the compensatory adaptation to GC-induced IR. Administration of high doses of prednisolone (30 mg) or dexamethasone (2-15 mg) to healthy individuals for prolonged periods (up to 15 days and up to 4 days respectively) resulted in normoglycaemia or a modest increase in fasting glycaemia (Beard et al 1984, Schneiter & Tappy 1998, Hollindgal et al 2002, Willi et al 2002, Nicod et al 2003, Ahrén 2008, van Raalte et al 2010, Petersons et al 2013. Importantly, in most of these studies, volunteers developed hyperinsulinaemia.…”

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

“…Excess GCs in circulation, such as occurs during Cushing disease or chronic GC therapy, promote both visceral fat deposition and hepatic insulin resistance (45,46). An increase in hepatic insulin resistance contributes to hyperglycemia in mouse models and in human subjects (47,48).…”

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

“…GCs are known to increase insulin resistance by facilitating hepatic glucose production and reducing peripheral glucose disposal (14)(15)(16). As a result, the use of GCs is associated with a risk of development or worsening of glucose intolerance, which is well known as one of the major adverse effects of GC therapy (17).…”

“…hepatic glucose production and reducing peripheral glucose disposal (14)(15)(16). In healthy humans, it has been reported that insulin secretion is two-to fourfold increased to compensate increased insulin resistance after short-term GC administration (21)(22)(23).…”